Azithromycin, 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A (IUPAC name: N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A), is an azalide-based semisynthetic macrolide antibiotic of formula (I) which is very effective in treating respiratory organ diseases, sexual contact infection, skin infection diseases and the like, as disclosed in U.S. Pat. Nos. 4,517,359 and 4,474,768 (Kirst and Sides, Antimicrob. Agents Chemother., 33, 1419(1989)):

Generally, azithromycin is prepared by conducting conventional Eschweiler-Clarke reductive N-methylation (Eschweiler and Clarke, Org. React., 5, 290(1945)) of the 9a-positon of 9-deoxo-9a-aza-9a-homoerythromycin A of formula (II), as described in U.S. Pat. No. 4,517,359, or by protecting the 3′-nitrogen of 9-deoxo-9a-aza-9a-homoerythromycin A of formula (II) with N-oxide, conducting N-methylation of the 9a-position thereof and then removing the N-oxide protecting group, as described in U.S. Pat. No. 4,474,768. The compound of formula (II) is thus a very important precursor in the preparation of azithromycin.

9-Deoxo-9a-aza-9a-homoerythromycin A of formula (II) may be prepared by reducing 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-homoerythromycin A (simply, 6,9-imino ether) of formula (III) which is prepared from erythromycin A 9-oxime in accordance with a conventional method (Djokic et al., J. Chem. Soc. Perkin Trans. I, 1881(1986)).

For example, U.S. Pat. Nos. 4,328,334 and 6,013,778 disclose a method of preparing the compound of formula (II) from the compound of formula (III) by way of conducting hydrogenation under a high hydrogen pressure in the presence of a rhodium(Rh), platinum(Pt), palladium(Pd) or ruthenium(Ru) metal or metal oxide catalyst; and Austrian Patent No. 8,600,536, by way of conducting electrical reduction. However, these methods have the problem that they require the use of an expensive precious metal catalyst and a high hydrogen pressure of 65 psi or higher, or that electrical reduction is not suitable for mass-production.
U.S. Pat. No. 4,328,334 discloses a method of preparing the compound of formula (II) by reducing the compound of formula (III) in a methanol solution maintained at 4° C. with a reducing agent such as NaBH4. However, this method requires a large excess amount of NaBH4 (16 mole equivalents or more) and the reduction product existing in the form of a borate complex must be subjected to further hydrolysis using an inorganic acid such as hydrochloric acid, the hydrolysis reaction inducing a side reaction to produce a large -quantity of impurities (Djokic et al., J. Chem. Soc. Perkin Trans. I, 1881(1986)).
International Publication Patent No. WO 94/26758 teaches that 9-deoxo-9a-aza-9a-homoerythromycin A of formula (II) may be prepared by hydrogenating erythromycin A 9-oxime or 9-deoxo-11-deoxy-9,11-epoxy-9,9a-didehydro-9a-aza-homoerythromycin (simply, 9,11-imino ether) of formula (IV) prepared from 6,9-imino ether of formula (III) under a high pressure in the presence of PtO2. However, this method suffers from a high manufacturing cost.

Therefore, there exists a demand for a simple method which is capable of providing 9-deoxo-9a-aza-9a-homoerythromycin A of formula (II) in a simple, economic way.
Accordingly, the present inventors have endeavored to develop such a method and have found that pure crystalline hydrate of 9-deoxo-9a-aza-9a-homoerythromycin A of formula (II) can be prepared in a high yield by reducing 6,9-imino ether of formula (III) with a small amount of NaBH4 at −20 to −10° C. and treating the reaction mixture with an acidic solution of citric acid, followed by neutralization.